Soluble receptor for advanced glycation end products(sRAGE)acts as a decoy sequestering of RAGE ligands,thus preventing the activation of the ligand-RAGE axis linking human diseases.However,the molecular mechanisms un...Soluble receptor for advanced glycation end products(sRAGE)acts as a decoy sequestering of RAGE ligands,thus preventing the activation of the ligand-RAGE axis linking human diseases.However,the molecular mechanisms underlying sRAGE remain unclear.In this study,THP-1 monocytes were cultured in normal glucose(NG,5.5 mmol/L)and high glucose(HG,15 mmol/L)to investigate the effects of diabetesrelevant glucose concentrations on sRAGE and interleukin-1β(IL-1β)secretion.The modulatory effects of epigallocatechin gallate(EGCG)in response to HG challenge were also evaluated.HG enhanced intracellular reactive oxygen species(ROS)generation and RAGE expression.The secretion of sRAGE,including esRAGE and cRAGE,was reduced under HG conditions,together with the downregulation of a disintegrin and metallopeptidase 10(ADAM10)and nuclear factor erythroid 2-related factor 2(Nrf2)nuclear translocation.Mechanistically,the HG effects were counteracted by siRAGE and exacerbated by siNrf2.Chromatin immunoprecipitation results showed that Nrf2 binding to the ADAM10 promoter and HG interfered with this binding.Our data reinforce the notion that RAGE and Nrf2 might be sRAGE-regulating factors.Under HG conditions,the treatment of EGCG reduced ROS generation and RAGE activation.EGCG-stimulated cRAGE release was likely caused by the upregulation of the Nrf2-ADAM10 pathway.EGCG inhibited HG-mediated NLRP3 inflammasome activation at least partly by stimulating sRAGE,thereby reducing IL-1βrelease.展开更多
Objective:To study the effect of Yigan capsule on the expression of high mobility group protein B1(HMGB1),nuclear factor-B(NF-κB)and receptor for advanced glycation end products(RAGE)in anti-tuberculosis drug-induced...Objective:To study the effect of Yigan capsule on the expression of high mobility group protein B1(HMGB1),nuclear factor-B(NF-κB)and receptor for advanced glycation end products(RAGE)in anti-tuberculosis drug-induced liver injury(ATB-DILI),and to explore its protective effect and mechanism on ATB-DILI,so as to provide experimental basis for the clinical application of Yigan capsule.Methods:Twenty-four rats were divided into two groups.Except for the blank group(n=6),the other 18 rats were given isoniazid(INH)+rifampicin(RFP)(50 mg/kg.d)for 4 weeks.Then 18 rats were randomly divided into three groups(model group,low dose group of Yigan capsule and high dose group of Yigan capsule)according to 6 rats in each group.The blank group and the model group were given 0.9%sodium chloride solution by intragastric administration.The low dose group of Yigan capsule was 0.468 g/kg,and the high dose group of Yigan capsule was 1.872 g/kg[1].After 4 weeks,the pathological changes of liver were observed by HE staining.The contents of ALT,AST,ALP,γ-GT and TBIL were detected.The expression of HMGB1,NF-κBp65 and RAGE protein was detected by IHC.The expression levels of HMGB1,NF-κBp65,RAGE,TNF-αand IL-1βwere detected by WB.Result:HE staining showed that the structure of the liver in the model group was disordered,the liver cells showed swelling and fusion,the number of inflammatory cells increased and accompanied by punctate necrosis,while the above pathological changes in each treatment group of Yigan capsule were significantly improved.The contents of ALT,AST,ALP,γ-GT and TBIL in the model group were higher than those in the blank group(P<0.05).The contents of ALT,AST,ALP,γ-GT and TBIL in each treatment group were significantly lower than those in the model group(P<0.05).Compared with the blank group,the expression levels of TNF-αand IL-1βin the model group were increased(P<0.05),and the expression levels of HMGB1,NF-κBp65 and RAGE were increased(P<0.05).Compared with the model group,the expression levels of TNF-αand IL-1βin each treatment group of Yigan capsule decreased(P<0.05),and the expression of HMGB1,NF-κBp65 and RAGE decreased(P<0.05).Conclusion:Yigan capsule may inhibit the secretion of inflammatory factors through HMGB1/RAGE/NF-κBp65 signaling pathway,thus protecting ATB-DILI.展开更多
目的:本研究通过检测结肠癌组织晚期糖基化终末产物受体(the receptor for advanced glycation end product,RAGE)和血清可溶性RAGE(soluble RAGE,sRAGE)的表达水平,探讨其在结肠癌发生、发展过程中的作用及其临床意义。方法:本研究纳...目的:本研究通过检测结肠癌组织晚期糖基化终末产物受体(the receptor for advanced glycation end product,RAGE)和血清可溶性RAGE(soluble RAGE,sRAGE)的表达水平,探讨其在结肠癌发生、发展过程中的作用及其临床意义。方法:本研究纳入49例非糖尿病结肠癌(I、II、III期)患者,以免疫组织化学评分法(immunohistochemical score,IHS)评价结肠癌RAGE表达水平,以ELISA法检测患者外周血血清sRAGE浓度。结果:结肠癌组织RAGE表达水平(IHS为1.24±0.48)显著高于癌周组织(IHS为0.50±0.25)(P<0.05),III期(IHS为1.42±0.51)显著性高于I期(IHS为1.01±0.35)(P<0.05)和II期(IHS为1.11±0.42)(P<0.05);低分化结肠癌组织(IHS为1.58±0.49)显著高于中分化(IHS为1.08±0.45)(P<0.05)和高分化结肠癌组织(IHS为1.02±0.27)(P<0.05)。结肠癌患者血清sRAGE表达水平术前、术后分别为(344.77±68.06)ng/L、(265.43±76.85)ng/L,二者相比有显著性差异(P<0.05),而且分别与健康志愿者sRAGE(149.97±30.12)ng/L相比有显著性差异(P<0.05),但sRAGE表达水平与TNM分期、结肠癌组织分化程度没有关联。结肠癌组织RAGE高表达患者术前血清sRAGE浓度(415.02±85.08)ng/L高于中表达(334.26±44.56)ng/L和低表达(335.95±78.48)ng/L患者(P<0.05)。结论:结肠癌组织RAGE表达水平与分化程度呈负相关趋势,与TNM分期呈正相关趋势,作为术后诊断指标有一定的临床意义。血清sRAGE浓度与结肠癌组织RAGE表达水平呈正相关趋势,但与TNM分期和结肠癌组织分化程度没有关联,作为术前诊断指标仅能代表结肠癌风险,但无法考量结肠癌的恶性程度和进展情况。展开更多
文摘Soluble receptor for advanced glycation end products(sRAGE)acts as a decoy sequestering of RAGE ligands,thus preventing the activation of the ligand-RAGE axis linking human diseases.However,the molecular mechanisms underlying sRAGE remain unclear.In this study,THP-1 monocytes were cultured in normal glucose(NG,5.5 mmol/L)and high glucose(HG,15 mmol/L)to investigate the effects of diabetesrelevant glucose concentrations on sRAGE and interleukin-1β(IL-1β)secretion.The modulatory effects of epigallocatechin gallate(EGCG)in response to HG challenge were also evaluated.HG enhanced intracellular reactive oxygen species(ROS)generation and RAGE expression.The secretion of sRAGE,including esRAGE and cRAGE,was reduced under HG conditions,together with the downregulation of a disintegrin and metallopeptidase 10(ADAM10)and nuclear factor erythroid 2-related factor 2(Nrf2)nuclear translocation.Mechanistically,the HG effects were counteracted by siRAGE and exacerbated by siNrf2.Chromatin immunoprecipitation results showed that Nrf2 binding to the ADAM10 promoter and HG interfered with this binding.Our data reinforce the notion that RAGE and Nrf2 might be sRAGE-regulating factors.Under HG conditions,the treatment of EGCG reduced ROS generation and RAGE activation.EGCG-stimulated cRAGE release was likely caused by the upregulation of the Nrf2-ADAM10 pathway.EGCG inhibited HG-mediated NLRP3 inflammasome activation at least partly by stimulating sRAGE,thereby reducing IL-1βrelease.
基金Scientific Research Project of Heilongjiang Provincial Education Department(No.12531608)。
文摘Objective:To study the effect of Yigan capsule on the expression of high mobility group protein B1(HMGB1),nuclear factor-B(NF-κB)and receptor for advanced glycation end products(RAGE)in anti-tuberculosis drug-induced liver injury(ATB-DILI),and to explore its protective effect and mechanism on ATB-DILI,so as to provide experimental basis for the clinical application of Yigan capsule.Methods:Twenty-four rats were divided into two groups.Except for the blank group(n=6),the other 18 rats were given isoniazid(INH)+rifampicin(RFP)(50 mg/kg.d)for 4 weeks.Then 18 rats were randomly divided into three groups(model group,low dose group of Yigan capsule and high dose group of Yigan capsule)according to 6 rats in each group.The blank group and the model group were given 0.9%sodium chloride solution by intragastric administration.The low dose group of Yigan capsule was 0.468 g/kg,and the high dose group of Yigan capsule was 1.872 g/kg[1].After 4 weeks,the pathological changes of liver were observed by HE staining.The contents of ALT,AST,ALP,γ-GT and TBIL were detected.The expression of HMGB1,NF-κBp65 and RAGE protein was detected by IHC.The expression levels of HMGB1,NF-κBp65,RAGE,TNF-αand IL-1βwere detected by WB.Result:HE staining showed that the structure of the liver in the model group was disordered,the liver cells showed swelling and fusion,the number of inflammatory cells increased and accompanied by punctate necrosis,while the above pathological changes in each treatment group of Yigan capsule were significantly improved.The contents of ALT,AST,ALP,γ-GT and TBIL in the model group were higher than those in the blank group(P<0.05).The contents of ALT,AST,ALP,γ-GT and TBIL in each treatment group were significantly lower than those in the model group(P<0.05).Compared with the blank group,the expression levels of TNF-αand IL-1βin the model group were increased(P<0.05),and the expression levels of HMGB1,NF-κBp65 and RAGE were increased(P<0.05).Compared with the model group,the expression levels of TNF-αand IL-1βin each treatment group of Yigan capsule decreased(P<0.05),and the expression of HMGB1,NF-κBp65 and RAGE decreased(P<0.05).Conclusion:Yigan capsule may inhibit the secretion of inflammatory factors through HMGB1/RAGE/NF-κBp65 signaling pathway,thus protecting ATB-DILI.
文摘目的:本研究通过检测结肠癌组织晚期糖基化终末产物受体(the receptor for advanced glycation end product,RAGE)和血清可溶性RAGE(soluble RAGE,sRAGE)的表达水平,探讨其在结肠癌发生、发展过程中的作用及其临床意义。方法:本研究纳入49例非糖尿病结肠癌(I、II、III期)患者,以免疫组织化学评分法(immunohistochemical score,IHS)评价结肠癌RAGE表达水平,以ELISA法检测患者外周血血清sRAGE浓度。结果:结肠癌组织RAGE表达水平(IHS为1.24±0.48)显著高于癌周组织(IHS为0.50±0.25)(P<0.05),III期(IHS为1.42±0.51)显著性高于I期(IHS为1.01±0.35)(P<0.05)和II期(IHS为1.11±0.42)(P<0.05);低分化结肠癌组织(IHS为1.58±0.49)显著高于中分化(IHS为1.08±0.45)(P<0.05)和高分化结肠癌组织(IHS为1.02±0.27)(P<0.05)。结肠癌患者血清sRAGE表达水平术前、术后分别为(344.77±68.06)ng/L、(265.43±76.85)ng/L,二者相比有显著性差异(P<0.05),而且分别与健康志愿者sRAGE(149.97±30.12)ng/L相比有显著性差异(P<0.05),但sRAGE表达水平与TNM分期、结肠癌组织分化程度没有关联。结肠癌组织RAGE高表达患者术前血清sRAGE浓度(415.02±85.08)ng/L高于中表达(334.26±44.56)ng/L和低表达(335.95±78.48)ng/L患者(P<0.05)。结论:结肠癌组织RAGE表达水平与分化程度呈负相关趋势,与TNM分期呈正相关趋势,作为术后诊断指标有一定的临床意义。血清sRAGE浓度与结肠癌组织RAGE表达水平呈正相关趋势,但与TNM分期和结肠癌组织分化程度没有关联,作为术前诊断指标仅能代表结肠癌风险,但无法考量结肠癌的恶性程度和进展情况。
